pRNA Nanoparticles for Therapeutic Applications Kylin Therapeutics is developing a proprietary small interfering RNA (siRNA) delivery platform technology inspired by a naturally occurring molecule called packaging RNA (pRNA). siRNA holds tremendous potential for a number of therapeutic applications, but siRNA will never realize its full promise without an effective way to deliver siRNA molecules to diseased tissues. pRNA is a purely RNA-based molecule that can be found in the RNA-packaging motor of the 29 bacteriophage. pRNA is a hexameric structure that serves as an essential gear in the RNA-packaging machinery. Targeting mechanisms, therapeutic payloads, and imaging/diagnostic agents can all be incorporated into the versatile monomer subunits of pRNA. Targeting or `homing'molecules including small molecules (ie folate) and receptor binding aptamers can be easily integrated into pRNA subunits. Kylin has extensively demonstrated that therapeutic payloads like siRNA, ribozymes, and aptamers all maintain their structure and function when designed into pRNA. Fluorescent imaging agents (ie FITC and Rhodamine) have also been incorporated successfully. Kylin has further developed pRNA technology so that all these capabilities can be combined, in an interchangeable fashion, into one nanoparticle. Kylin has designed monomer units of pRNA to form dimers, trimers, and hexamers. Within each multiplex, any combination of homing molecule, therapeutic payload, and/or imaging/diagnostic agent can be easily self- assembled into a multi-functional nanoparticle. By incorporating siRNAs into this versatile platform, Kylin can effectively deliver siRNAs to target tissues. The purpose of this Phase I SBIR project is to optimize pRNA nanoparticles in vitro and provide in vivo evidence toward their effectiveness against cancer. These studies will set the foundation for larger, multi-animal GLP-level in vivo studies in a Phase II application. PUBLIC HEALTH RELEVANCE: pRNA Nanoparticles for Therapeutic Applications Kylin Therapeutics utilizes a unique drug delivery platform to develop novel therapeutics that can safely and effectively treat a wide range of diseases including cancer.